End-stage renal disease (ESRD) remains a major health problem in the United States, with an incidence that has been increasing steadily for more than a decade. More than 67% of ESRD is associated with hypertension and/or diabetes. The causes for these associations are not known. However, there is increasing evidence that susceptibility genes are likely to play a major role in determining a patient?s predisposition to ESRD. We have developed a comprehensive research program including genetics, genomics, rat transgenics and mechanism-based physiology to study the complex interaction between hypertension and susceptibility genes for renal disease. Here we propose to focus these tools on the following specific aims: 1. Complete the positional cloning of the Rf-1 gene. We identified this important QTL and propose to combine mapping and comparative genomics to locate the specific gene. 2. Determine pathways involved in the renal disease process using microarray technology. By identifying genes differentially expressed in normal and diseased kidney over the time course of ESRD development, we will see how gene expression is modified in the disease process. 3. Test our hypothesis that Rf-1 causes impaired renal autoregulation due to a lack of myogenic tone, resulting in glomerular hypertension and renal damage. We will also pursue mechanism-based studies of the QTL?s Rf-2, -3 and -5. 4. Study the Rf-1 locus by constructing transgenic rats carrying YACs. This will allow a direct test of any genes within the YAC. Transgenics will also be used to validate Rf-1. 5. Use comparative genomics to study human homologue of the Rf-1 region, Rf-1 gene and other candidate genes in humans. Using affected/unaffected human sibpairs, we will use SNP and sequence analysis to determine if individuals exhibiting ESRD show a significant association with sequence variants in candidate genes.